Amide derivatives of isoxazole carboxylic acids



Patented Aug. 9, 1938 e rs:

t ili ht? iii FEE

All HD1331 DEREVATWES 01F ISQXAhOLE GAR/- BGXYLICG AGIDS Max Heifer, Basel, Switzerland, assignor to lllloffmann-llla Roche llnc, Nutley, N. .l., a corpcration of New Jersey No Drawing. Application January 25, 1937, Se-

rial No. 122,321... 1936 4 Claims.

1 CRa in which one of the residues R1, R2, R3 indicates a carboxyl group, the remainder allryl residues or hydrogen, into reactive acid derivatives, e. g. into acid chlorides and allowing these compounds to react with secondary amines, dialkyl substituted amides oi isoxazole carbcxylic acids having valuable therapeutic properties are obtained.

:70 It has now been found that other compounds with an imino group capable of being acylated also form amide-like compounds with isoxazole carboxylic acids which exert a pronounced action as circulatory stimulants. Secondary amines of the aromatic series, compounds with an imino group as part of the heterocyclic ring, as Well as mono-substituted urethanes are examples of such imino compounds.

For the manufacture of the new compounds reactive derivatives of isoxazole carboxylic acids, such as acid chlorides, are caused to react with the required imino'compounds, if necessary in presence of a solvent capable of combining with acids or in presence of alkali.

The new compounds are to be used in medicine.

Example 1 0 cm OHa-(f fil-CHa O--N distils over as a viscous oil at 198 C. under a lin Switzerland March 2-0,

pressure of 11 mm. and, after some time, sets to prismatic crystals melting at 42-43 C. It is easily soluble in alcohol, ether or benzene, difi'lcultly soluble in water.

Example 2 145 parts by weight of -methyl-isoxazole-3- carboxylic acid chloride are caused to react with 214 parts by weight of methyl aniline as described in Example 1. After distilling oii the ether, a syrup, which soon crystallizes, remains. Purification may be effected by recrystallizing the methyl anilide of 5-methyl-isoxazole-3-carboxylic acid having the structural formula from a little benzene. In this manner it tained in the form of colourless prisms ing at 763*." C., which are easily soluble cohol or ether, diiilcultly soluble in water.

Example 3 While cooling nd stirring, 159 parts by weight of 3,5-dimethyl--isoxascle-e-carboxylic acid chloride are dropped into a mixture of 121 parts by weight of inethyl-benzyl-amine, 500 parts by weight of ether and 250 parts by weight of a 20 per cent. solution of caustic soda. The ether layer is removed, dried and the ether distilled off. The residue distils at 216-217" C. under a pressure of 11 mm. The methyl-benzyl-amide of 3,5- dimethyl-isoxazole-4-carboxylic acid having the structural formula is obtained in the form of a viscous yellowish oil, which soon solidifies to crystals. It melts at 51-52 C., dissolves readily in alcohol, ether and benzene, but with difficulty in water.

Example 4 159 parts by weight of 3,5-dimethyl-isoxazolei-carboxylic acid are caused to react with 226 parts by Weight of p-dimethylamino-phenylbenZyl-amine in a manner analogous to that described in Example 3. Into the ethereal solution of the p-dimethylaminophenyl-benzene-amide of the 3,5-dimethyl-isoxazole-4-carboxy1ic acid thus obtained dry hydrochloric acid having the structural formula I CH: C CH2C6H5 gas is introduced. Thereby, the hydrochloride of the base precipitates and soon becomes crystalline. It melts at 198-199 C. and is soluble in n/1000 acid forming a clear solution. The free base melts at 76 C.

Example 5 separates in the crystalline state. It crystallizes from dilute acetic acid and then melts at l16-117 C.

Example 6 To a cooled and stirred mixture of 9'7 parts by weight of Z-methyl-piperidine, 500 parts by weight of benzene and 200 parts by weight of a per cent. solution of caustic soda, 159 parts by weight of 3,5-dimethyl-isoxazole-l-carboxylic acid chloride are added dropwise. The benzene layer is removed, dried with anhydrous potash and the residue remaining after distilling off the benzene distilled in vacuo. The 3,5-dimethy1- isoxazolel-carboxylic-acid- 2-methyl-piperidide having the structural formula melts at 40-41 C.; it distills as a light-coloured viscous oil at 189-191 C. under a pressure of 11 mm. and possesses a pronounced action as a circulatory stimulant.

Example 7 159 parts by weight of 3,5-dimethyl-isoxazole- 4-carboxylic acid chloride are caused to react with 109 parts by weight of 2,6-dimethyl-piperidine in the manner described in Example 6. The resulting 3,5 dimethyl isoxazole -4- carboxylicacid-2'-6-dimethyl-piperidide having the structural formula CH-OH:

CON CH2 OFF-OH: 311:

CHs-C C-CH: 1't

is distilled at 192-195" C. under a pressure of 11 mm. It is an oil difiicultly soluble in water. The action as a circulatory stimulant is about the same as that of the methyl piperidide.

Example 8 159 parts by weight of 3,5-dimethyl-isoxazolel-carboxylic acid chloride are made to react upon 117 parts by weight of ethylcarbamic acid ethylester as described in Example 5. The 3,5-dimethyl-4isoxazolyl-N-ethyl-urethane having the structural formula is obtained in needles melting at 117-118 C.

I claim: 1. As a medicinal remedy a compound of the general formula wherein one of the radicals R1, R2 and R3- represents the group Z.CO wherein Z is selected from the group consisting of wherein X is an alkyl radical and Y is selected from the group consisting of an aryl radical of the benzene series, an aralkyl radical of the benzene series and a carboxylic lower aliphatic ester radical and T:N- wherein T: represents an alkylene radical forming a heterocyclic ring with the N, and the remaining R radicals are selected from the group consisting of hydrogen and lower alkyl hydrocarbon radicals of the methane series, which compound acts as a circulatory stimulant.

2. As a medicinal remedy for use as a circulatory stimulant the methyl anilide of 3,5-dimethyl-isoXazole-4-carboxylic acid, melting at 42-43 C. and distilling as a viscous oil at 198 C. under a pressure of 11 mm.

3. As a medicinal remedy for use as a circulatory stimulant 3,5-dimethyl-isoXazole-4-carb0xylic acid2',6-dimethyl-piperidide, which distills at l92-l95 C. under a pressure of 11 mm.

4. As a medicinal remedy for use as a circulatory stimulant the 3,5-dimethyl-isoXazole-4-car boxylic-acid-Z'-methyl-piperidide melting at 40-41 C., distilling as a light-coloured viscous oil at 189-491 C. under a pressure of 11 mm.

MAX HOFFER. 

